What types of OCs are associated with Schizophrenia?
Andrey Nailor, M.D.·Published 14 May 2009·11 min read
Key points
OCs have been linked to the etiology of schizophrenia since the 1960s when Lane and Albee (1966) first observed that birthweights of 52 patients with schizophrenia were lower than those of their siblings without schizophrenia.
There have now been multiple reviews (see References and Recommended Readings) that show that fetal hypoxia is likely involved in a variety of OCs associated with schizophrenia.
The role of prenatal infection in the etiology of schizophrenia has been repeatedly documented through a series of epidemiological and, more recently, serological studies.
Since the 1960s dozens of articles have linked aberrant events during the pre- and perinatal periods to schizophrenia.
OCs have been linked to the etiology of schizophrenia since the 1960s when Lane and Albee (1966) first observed that birthweights of 52 patients with schizophrenia were lower than those of their siblings without schizophrenia. Despite the fact that the differences were relatively small (about 175 grams), and few of the schizophrenia patients had birthweights that were less than 2,500 grams (the criterion for low birthweight), this study raised the possibility that events during the very early stages of life may have longlasting neurobiological effects, potentially contributing to the causes of schizophrenia.
Since the 1960s dozens of articles have linked aberrant events during the pre- and perinatal periods to schizophrenia. Investigations into this area have taken many forms, such as following genetically at-risk individuals (e.g., offspring of patients with schizophrenia and unaffected siblings of patients with schizophrenia), comparing the prevalence of OCs in patients with schizophrenia and controls (often using maternal recall), and, last, taking advantage of population databases and registries containing detailed information about the pre- and perinatal periods, as well as information regarding psychiatric statuses. Given the variety of study procedures, the conflicting results from many of the investigations exploring the role of obstetric events in the etiology of schizophrenia are not surprising. For this reason, studies using population registries (e.g., in Scandinavia) have been especially useful in providing detailed, prospective obstetric information, in addition to having large enough samples to detect meaningful results.
Recent findings from population-based studies have had the added advantage of exploring molecular pathways in schizophrenia by examining stored maternal blood sera from the pre- and perinatal periods. For our purposes in this chapter, we briefly summarize the types of OCs that have been associated with schizophrenia; however, we focus on the more recent, population-based results, especially those using serological data.
Many OCs have been linked to schizophrenia and can grossly be divided into categories of complications during pregnancy, fetal and neonatal underdevelopment, and birth complications. A meta-analysis of eight population-based studies found that diabetes during pregnancy, birthweight less than 2,000 grams, emergency caesarean section, congenital malformations, uterine atony, rhesus variables (comprising rhesus [Rh] incompatibility, Rh-negative mother, Rh antibodies), fetal asphyxia, bleeding during pregnancy, birthweight less than 2,500 grams, preeclampsia, placental abruption, head circumference less than 32 cm, and nonspontaneous delivery all were associated with increased risk of schizophrenia. Beyond these eight studies, a large body of research has linked multiple infections during pregnancy and maternal stress to schizophrenia outcome in offspring.
Given the vast number of OCs linked to schizophrenia, the question arises as to whether any insult in a genetically vulnerable individual could lead to schizophrenia outcome, or whether some underlying mechanisms link these obstetric events to each other.
Written and revised by
Andrey Nailor, M.D.
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Two pathways have been linked to many of the obstetric abnormalities associated with schizophrenia: (1) decreased oxygen to the fetus, termed fetal hypoxia or asphyxia, and (2) maternal immune responses to infection and other insults during pregnancy.
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Fetal Hypoxia
There have now been multiple reviews (see References and Recommended Readings) that show that fetal hypoxia is likely involved in a variety of OCs associated with schizophrenia. Specifically, OCs associated with schizophrenia, such as emergency caesarian section, bleeding during pregnancy, and preeclampsia, have all been associated with fetal hypoxia.
To test the strength of the relationship between hypoxia-associated OCs and schizophre- nia onset in offspring, two studies used a hypoxia-associated OCs scale, including both indirect and direct indicators of hypoxia. Direct hypoxia-associated complications included events such as blue at birth, required resuscitation, neonatal cyanosis, and neonatal apnea. Indirect complications were selected based on validation with direct measures of hypoxia from previous studies and included abnormalities of fetal heart rate or rhythm, umbilical cord knotted or wrapped tightly around neck, third trimester bleeding, placental hemorrhaging or infarcts, an excessive amount of amniotic fluid (polyhydramnios), meconium1 in amniotic fluid, and breech presentation. Both studies found that hypoxia-associated OCs were associated with schizophrenia outcome in offspring, especially when patients exhibited disease onset at an early age.
Hypoxia-associated OCs also have been found to differentiate between siblings with and without schizophrenia, suggesting that in the presence of a common genetic background (i.e., sibship), fetal hypoxia increases the likelihood of later developing schizophrenia. Nevertheless, fetal hypoxia is unlikely to lead to schizophrenia on its own; therefore, a genetic factor associated with schizophrenia likely renders the fetal brain particularly vulnerable to the effects of hypoxia. This hypothesis is supported by brain imaging studies, in which hypoxia-associated OCs predicted ventricular enlargement in patients with schizophrenia but not among their unaffected siblings and controls at low genetic risk for schizophrenia. Similarly, one study compared hippocampal volumes of patients with schizophrenia, their unaffected siblings, and nonschizophrenia comparison subjects, and found a stepwise decrease in hippocampal volumes with increased genetic liability for the disorder. A history of hypoxia-associated OCs led to further reductions in hippocampal volumes among patients with schizophrenia, suggesting that genetic contributions to hippocampal volume reductions in patients with schizophrenia were worsened by a history of fetal hypoxia. The aforementioned studies support a gene - environment interaction model, in which an early hypoxic event adds to or interacts with a genetic vulnerability for schizophrenia, leading to a form of schizophrenia characterized by earlier age of onset and greater neuroanatomical abnormalities.
Independently of a genetic liability for schizophrenia, fetal hypoxia has been found to affect many of the same neural substrates implicated in schizophrenia, depending on the severity and duration of the hypoxic event, as well as the period of gestation. In sheep, fetal hypoxia has been found to disrupt neuronal development and connections in the hippocampus, cerebellum, and visual cortex. When the duration of the hypoxia was increased to 20 days during late gestation, abnormalities were found in the cerebellum, as well as white matter lesions. Shorter periods of hypoxia during midgestation were associated with reductions in cortical white matter, as well as hippocampal density reductions.
Brains of rat pups exposed to perinatal hypoxia during the last day of gestation showed myelination deficits in multiple brain regions, including the hippocampus and cerebellum, suggesting that hypoxia may also affect neuronal signal speed. In addition, findings from rat studies have linked perinatal oxygen insufficiency with dopamine abnormalities in the prefrontal cortex, nucleus accumbens, and striatum.
In humans, fetal hypoxia has been linked to a series of motor and cognitive deficits in children. Children exposed to mild fetal hypoxia exhibited no detectable motor or cognitive deficits later in childhood; however, exposure to moderate fetal hypoxia led to speech, language, motor, verbal, and overall cognitive deficits. Furthermore, survivors of moderate hypoxia were more likely to be behind more than one grade level compared to children in their age group. The more severe cases of fetal hypoxia often lead to neonatal death or cerebral palsy. Thus, infants exposed to moderate and severe fetal hypoxia are at risk for physical and mental impairment, as well as worsened school performance even in the absence of a genetic vulnerability for schizophrenia.
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Infection during Pregnancy
The role of prenatal infection in the etiology of schizophrenia has been repeatedly documented through a series of epidemiological and, more recently, serological studies. Season of birth, especially during winter - spring months, has been consistently linked with schizophrenia outcome, and these months are typically associated with a higher incidence of infection. Among epidemiological studies, various prenatal infections, including influenza and rubella exposure, have been linked to schizophrenia outcome, although there have been some conflicting findings.
More recently, serological data confirming maternal infection during pregnancy have emerged in schizophrenia research. These studies provide major methodological advancements over previous investigations, given that biological indicators of infection can provide a better estimation of positive cases, as well as assess the timing and severity of the infection. These data have come from banked maternal sera from two large birth cohort studies in the United States that followed women throughout the prenatal period and subsequently followed their offspring during the 1950s and 1960s. Among these studies, herpes simplex virus - 2 (HSV-2), influenza, maternal genital and reproductive infection (including endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, "venereal disease," and gonorrhea) antibodies have been linked to schizophrenia spectrum disorders. Prenatal exposure to the parasitic infection Toxoplasma gondii was linked to schizophrenia in one study, but another study failed to replicated this finding, which may have been due to a relatively small sample size (including 27 psychotic offspring, only 13 of whom were diagnosed with schizophrenia).
With the exception of the parasite T. gondii, viral infections rarely cross the placenta; therefore, the damaging effects of fetal exposure to most viral infections likely involve multiple molecular pathways, a primary one being the mother's immune response to viral infections. During pregnancy, many immunological changes to protect the fetus from the mother mounting an immune response to a genetically dissimilar entity. Many of these changes involve signaling proteins called cytokines, which are considered the hormones of the immune system and, among other functions, are essential in combating infections.
Although there are exceptions, there seems to be a shift in immune functioning during pregnancy, with preferential production of helper T cell (Type 2) Th2 cytokines, such as interleukin - 4 (IL-4), interleukin - 5 (IL-5), and interleukin - 10 (IL-10), that are mainly involved in the stimulation of B cells and antibody responses. The relative increase in Th2 cytokines during pregnancy has been associated with a down-regulation of Th1 cytokines, such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin - 2 (IL-2), which are involved in cell-mediated immunity and inflammation (proinflammatory cytokines), thereby potentially decreasing the mother's ability to respond to viral infection.
In addition to the possibility that the fetus is more vulnerable to infection due to a shift in maternal immune functioning, studies suggest that the maternal antiviral response may contribute directly to the neuronal abnormalities found in offspring exposed prenatally to infection, with particular importance placed on the role of proinflammatory cytokines. Pregnant mice injected with a sham virus, capable of producing an antiviral reaction, had offspring with cognitive deficits similar to those found among patients with schizophrenia, such as deficits in prepulse inhibition (thought to be a measure of sensorimotor gating). In concert with these findings, rats prenatally exposed to proinflammatory cytokines have a multitude of brain abnormalities similar to those found among patients with schizophrenia, such as abnormalities in the hippocampus and cortex. In humans, exposure to elevated cytokines during pregnancy has been associated with neurodevelopmental damage, such as periventricular leukomalacia, cerebral palsy, and mental retardation. In summary, these findings suggest that neuronal abnormalities associated with prenatal infection may be related to elevated proinflammatory cytokine production, even in the absence of a genetic diathesis for schizophrenia.
In addition to the direct neurotoxic effects of proinflammatory cytokines, growing evidence suggests a causal relationship between inflammation and multiple OCs found in the histories of patients with schizophrenia, including preterm delivery, preeclampsia, and fetal oxygen deprivation (hypoxia). As discussed earlier, fetal hypoxia leads to a series of neuronal abnormalities found among patients with schizophrenia, even in the absence of infection and in individuals at low genetic risk for schizophrenia. Therefore, fetal neuronal damage following exposure to inflammation may be in part a result of the damaging effects of fetal hypoxia.
Given the aforementioned studies, it is not surprising that investigators have begun to explore the possible relationship between fetal exposure to proinflammatory cytokines and schizophrenia outcome. This area of research is somewhat complicated by the dynamic nature of the immune system. Specifically, cytokines typically aggregate around the site of infection and/or injury; therefore, cytokine levels in blood serum typically do not accurately reflect either the constantly changing state of the immune system or the interactions between the mother's immune system and the developing fetus. Nevertheless, two studies have linked markers of inflammation from maternal serum to psychotic outcome in offspring. Specifically, interleukin-8 (IL-8) during second and third trimesters and TNF-alpha at the time of birth (both proinflammatory cytokines) have been linked to increased incidence of psychosis in offspring.
In addition to the direct neurotoxic effects of fetal exposure to proinflammatory cytokines, emerging evidence suggests that genetic polymorphisms found in schizophrenia populations may make certain individuals more susceptible to the negative effects of infection and inflammation. TNF-a (promoter region A2) and IL-1 complex [IL-1-alpha (-889) allele 2, IL-1-beta (-511) allele 1, and IL-1RA allele 1] genetic polymorphisms have been associated with schizophrenia outcome. These polymorphisms typically lead to both production of proinflammatory cytokines without any known infection (i.e., basal levels) and overproduction of proinflammatory cytokines in response to infection. Although individuals with these polymorphisms do not always develop schizophrenia, they appear to be more vulnerable to multiple diseases and infections. Therefore, it is possible that carriers of genetic polymorphisms associated with inflammation could be more vulnerable to the damaging effects of prenatal infection, thus increasing the likelihood of psychotic onset in adulthood; however, no studies have directly tested this gene - environment interaction.
Cumulatively, studies implicate a series of prenatal infections in the etiology of schizophrenia. Nevertheless, it appears as though the deleterious effects of exposure to prenatal infection may be more related to maternal immune responses to infection than to the direct effects of the pathogen, given that most pathogens do not cross the placenta.
Specifically, prenatal exposure to maternal proinflammatory cytokines has been found to alter multiple areas of the brain that have been implicated in schizophrenia, and these cytokines have been linked to psychotic outcome in offspring. In addition, genetic polymorphisms associated with overproduction of proinflammatory cytokines have been found in patients with schizophrenia, suggesting that individuals who later develop schizophrenia may be particularly vulnerable to infection and other prenatal insults. Last, both infection and proinflammatory cytokines have been linked to increased fetal hypoxia, which has been associated with schizophrenia and many of the brain abnormalities linked to the disorder. The availability of studies using serological data and the possibility of examining direct gene - environment interactions likely will lead to a much better understanding of the molecular pathways linking OCs to schizophrenia outcome, which is the starting point for developing treatment and early intervention strategies.
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